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Effects of amrinone and milrinone on calcium influx into the myocardium
Abstract:
We have examined the effects of milrinone on calcium influx into cardiac cells by testing its effects on three mechanisms of calcium entry: the slow inward calcium current, sodium-calcium exchange diffusion, and the passive calcium permeability of sarcolemmal membranes. Milrinone increased the magnitude of the slow inward calcium current in voltage-clamped calf cardiac Purkinje fiber. High concentrations of this agent also caused a small, inconsistent inhibition of calcium uptake mediated by sodium-calcium exchange in bovine cardiac sarcolemma membranes, but did not alter the time course of passive efflux of calcium from these vesicles. In conclusion, milrinone and its analogue amrinone appear to increase the entry of calcium into myocardial cells, primarily by increasing the influx of this cation during the slow inward calcium current. A small and sodium-calcium exchange may also influence calcium influx, particularly at high drug concentrations. The relationship existing between these effects and the inotropic responses produced by amrinone and milrinone is discussed.
Insights
Milrinone enhances calcium entry into heart cells, mainly by increasing the slow inward calcium current. This mechanism is key to its inotropic effects, with sodium-calcium exchange playing a minor role.
Area of Science:
- Cardiovascular Pharmacology
- Cell Physiology
Background:
- Understanding calcium influx mechanisms is crucial for developing cardiac drugs.
- Milrinone is a phosphodiesterase inhibitor used for heart failure.
Purpose of the Study:
- To investigate the effects of milrinone on cardiac calcium influx.
- To elucidate the specific mechanisms of calcium entry affected by milrinone.
Main Methods:
- Examined milrinone's impact on slow inward calcium current using voltage-clamped calf cardiac Purkinje fibers.
- Assessed effects on sodium-calcium exchange and passive calcium permeability in bovine cardiac sarcolemma vesicles.
Main Results:
- Milrinone significantly increased the slow inward calcium current magnitude.
- High milrinone concentrations showed minor, inconsistent inhibition of sodium-calcium exchange.
- Passive calcium efflux was not affected by milrinone.
Conclusions:
- Milrinone primarily increases myocardial calcium entry via the slow inward calcium current.
- Sodium-calcium exchange may contribute to calcium influx at high concentrations.
- These calcium influx effects are linked to the inotropic responses of milrinone and amrinone.